The matrix metalloproteinases (MMPs) are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72 kDa gelatinase, 92 kDa gelatinase, stromelysin-1, stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase, membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2. These enzymes share a common zinc-containing catalytic domain and a pro-sequence which maintains latency. A wide range of cells and tissues can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor-.alpha. (TNF-.alpha.). Different stimuli can induce overlapping yet distinct repertoires of MMPs and different cell types can respond to the same stimuli by expression of distinct combinations of MMPs. MMPs can attack the protein components of extracellular matrix such as collagens, vitronectin and elastin, and have recently been shown to process membrane proteins such as pro-TNF-.alpha. to release soluble TNF-.alpha.. MMPs are thought to play a central role in the pathology of inflammatory diseases such as rheumatoid arthritis as well as in the growth and metastasis of tumours.
Compounds which have the property of inhibiting the action of MMPs are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group or a carboxylic group respectively as their zinc binding groups. Many such known MMPs may be represented by the structural formula (IA) ##STR2##
in which X is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds.
The following patent publications disclose such MMP inhibitors:
US 4599361 (Searle) WO 95/04033 (Celltech) EP-A-2321081 (ICI) WO 95/04735 (Syntex) EP-A-0236872 (Roche) WO 95/04715 (Kanebo) EP-A-0274453 (Bellon) WO 95/06031 (Ilmmunex) WO 90/05716 (British Biotech) WO 95/09841 (British Biotech) WO 90/05719 (British Biotech) WO 95/12603 (Syntex) WO 91/02716 (British Biotech) WO 95/19956 (British Biotech) WO 92/09563 (Glycomed) WO 95/19957 (British Biotech) US 5183900 (Glycomed) WO 95/19961 (British Biotech) US 5270326 (Glycomed) WO 95/19965 (Glycomed) WO 92/17460 (SB) WO 95/22966 (Sanofi Winthrop) EP-A-0489577 (Celltech) WO 95/23790 (SB) EP-A-0489579 (Celltech) WO 95/32944 (British Biotech) EP-A-0497192 (Roche) WO 95/33709 (Roche) US 5256657 (Sterling) WO 96/06074 (British Biotech) WO 92/13831 (British Biotech) WO 96/16027 (Syntex/Agouron) WO 92/22523 (Research Corp) WO 96/16931 (British Biotech) WO 93/09090 (Yamanouchi) WO 96/23791 (Syntex) WO 93/09097 (Sankyo) WO 96/29313 (Procter & Gamble) WO 93/20047 (British Biotech) WO 96/33161 (British Biotech) WO 93/24449 (Celltech) WO 96/33165 (British Biotech) WO 93/24475 (Celltech) WO 96/33166 (DuPont Merck) EP-A-0574758 (Roche) WO 96/33968 (Fuji YKKK) EP-A-0575844 (Roche) WO 96/33991 (Sankyo) WO 94/02446 (British Biotech) WO 97/02239 (British Biotech) WO 94/02447 (British Biotech) WO 97/03966 (British Biotech) WO 94/21612 (Otsuka) WO 97/15553 (Sankyo) WO 94/21625 (British Biotech) WO 97/19053 (British Biotech) WO 94/24140 (British Biotech) WO 94/25434 (Celltech) WO 94/25435 (Celltech
M. A. Abreo et al. presented a poster entitled "Truncated Succinamide Hydroxamates With Nanomolar Potency against various MMPS" at the 213th ACS Meeting in San Francisco, Apr. 13-17, 1997. In that poster compounds of formula (IC) were disclosed: ##STR3##
wherein X is --COOH or --CONHOH, P.sub.1 is biphenylpropyl, R is hydroxymethyl and P.sub.2 is the side chain found in one of the following amino acids, namely serine, tert-butylglycine, histidine, O-benzylthreonine, phenylalanine, tyrosine, methionine, threonine, and 3-(3-pyridyl)alanine. Also disclosed were compounds of formula (IC) wherein X and P.sub.1 are as just defined, and P.sub.2 and R together with the carbon atom to which they are attached form a trans-cyclohexan-2-ol or glucosyl ring. The authors stated that the compound (IC), P.sub.2 =the histidine side chain and R=hydroxymethyl, showed good plasma levels after iv and oral dosing to mice. They also stated that the X-ray crystal structure of compound (IC), P.sub.2 =tert-butyl and R=hydroxymethyl, was obtained with stromelysin-1, and that the hydroxyl moiety in R makes an H-bond in the P.sub.3 area of the enzyme, while the tert-butyl group makes good hydrophobic contact in the P.sub.2 area.